3,17-dihydroxy-11-ketopregnines-20 and process



Patented Dec- 27, um

UNITED STATES PATENT OFFICE 2,492,189 SJ'I-DIHYDBOXY-ll-KETOPBEGNBVES-ZOAND PROCESS Lewis B. Sarett, Princeton, N. 3., assignor to Merck & 00.,Inc., Railway, N. 1., a corporation of New Jersey No Drawing Originalapplication July 14, 1945,

Serial No. 005.194. mum and this application February 23, 1948, SerialNo. 849,761

8 Claims. (01; 2M7.

' droxy pregnene. This application is a divisional of copendingapplication Serial No. 605,194 flied July 14, 1945, now abandoned.

This hormone is known to occur naturally in the adrenal cortex; it hasthe structural formula:

ZIGHlOH (Standard numbering of C-posltions.)

This formula, for purposes of convenience, is hereinafter reproducedbelow in the abbreviated form:

CHIOH OH: OK

2 droxyl) to the right of the 6-1! carbon side chain, thus CHaOH HOE ono in the latter case above the side chain, thus OH XCH=GH2 3. Thestereochemical relationship of rings A and B is indicated in theformulae by a solid line representing the valence bond in the cisconfiguration.

In accordance with the present invention it is now found this hormonecan be synthesized by reactions indicated as follows:

CH: CHI err-coin 11-00111 CH: CH8

on. "5... OH;

l acyl-halidoforming reagent cm cm H-G 0N; (EH-c ox 0H, CH:

MN on, on, no 110C A,H:0,H+ CH CH CH CH;

CH: CH: R0

v11 no no I xn m lnczcn cm H-NH, CH; CH OH OH 0 CH: CECE CH CH=CH1 O OCH 0 CH: CH:

VI HONO 1" 93 Y B0 I-HzO OH: H HO HOE 3 CH XIII XIV CH; acylatin l agentCHgX' AH OH BO CH CH: CH=CH2 VIII CH: CH:

OHa halogenating agent H 0 CH: CH:

\ xvI xv on 0H:

CH-CH:X' CH-CH;0R"

CH: CH3

n no

H CH; MOB" CH: VI IX OH: O; to XVII (Ll form XVI H ozonide, CHO

followed 7 B O R O CH: by (10- CH: hydrolysis composi- 0 tion O H H CH:CH:

CH-CHaOR' CH-CHzOH CH3 CH3 R R R"OH or 0\ (RIII)ZO vn l x CH: CH:

XVIII 7o XIX (Ix) HO HO oxidation oxidation 1. l

l hydrolysis (SH-0390B" OH-CHaOH H OH hydrol- CH yak OH 10 XXI XX minimc out CHIOE ('JHOH CH-CHgO 11"" on on:

1: droxy tint: on i on XXII XXIII o o I acylating agent I B"!!! R!!!" ano B!!!" 0 RH"! 011 on on. on i o\ CH X'" OH xxv XXIV CH,0 RIIIII R"!!!HORIIII! $HORIIII! OH; OH OH; /OH A o\ CH; pyridine CH XXVI XXV lhydrolysis OBOE CHzOH HOH H0H CH: /OH OH; OH 0 O z CH; (R010 CH:

XXVIII XXVII CHaOR' OH; OH CH:

CH: CH;

XXIX XXX lhydrolysis CHOH CH; 0H

In the above formulae. R, R, R", R', R"", R""', and Rs are acyl; X, X'and X" are halogen; and M is an alkali'metal or an alkaline earthmetal/2.

The reactions above indicated are conducted as follows:

3-hydroxy-ll-keto-bisnorcholanic acid (I) is aclylated producing3-acyloxy-ll-bisnorcholanic acid (11) which is treated with an agentcapable of converting an organic carboxylic acid to the correspondingacid halide, thus forming the acid halide of3-acyloxy-ll-keto-bisnorcholanic acid (III). Upon treatment of this acidhalide with an alkali metal azide or alkaline earth metal azide, theazide of 3-acyloxy-11-keto-bisnorcholanic acid (IV) is formed.Decomposition of this azide with an acidic aqueous solution produces3-acyloxy-11-keto-20-aminopregnane (V).

Upon treatment of this compound (V) with nitrous acid, a mixturecontaining predominantly A"--3-acyloxy-ll-keto-pregnene (VI) and A-3-acyloxy-11 -keto-pregnene (VII and a minor amount of3-acyloxy-11-keto-20-hydroxypregnane (VIII) results. The proportion ofthe desired compound (VI) present in this mixture can be increased bytreating the mixture with an aromatic sulfonyl halide followed byfurther treatment with a base to cause removal of the elements of thecoresponding aromatic sulfonic acid." The mixture of these compounds(VI) and (VII) or of (VI), (VII) and (VIII), is then treated with ozonefollowed by decomposition of the ozonide, producing3-acyloxy-11,17-diketoetiocholane (IX) andS-acyloxy-ll-keto-l'l-formyletiocholane (X).i Compound (X) is oxidizedto S-acyloxy-ll-ketoetiocholanic acid (XI) which is separated fromcompound (IX) by extraction with alkali.

Compound (IX) is hydrolyzed to form 3-hydroxy-11,17-diketoetiocholane(XII) which is treated with acetylene to form 3,17-dihydroxy- 11-keto-pregnine-2O (XIII). This compound (XIII) is catalyticallyhydrogenated to produce A -3,17 dihydroxy 11 ketopregnene (XIV) which isacylated to form A -3-acyloxy-17-hydroxy-lI-ketopregnene (XV), and thiscompound is halogenated to produce A -3-acyloxy-11- keto-21 halopregnene(XVI). When treated with an alkali metal salt or alkaline earth metalsalt of an organic acid, this compound yields A1730 3,2l-diacyloxy 11ketopregnene (XVII) which is hydrolyzed producing A -3,21-dihydroxy-ll-ketopregnene (XVIII). The latter product (XVIII) is partiallyesterified and the mono ester (XIX) thus produced is oxidized to convertthe unesterified hydroxy group in the 3 position to a keto group,thereby yielding the ester of A -3,11-diketo-21-acyloxy-pregnene (XX).This product (XX) is hydrolyzed and the A 3,11 diketo- 21-hydroxypregnene (XXI) thus formed is acylated producing A 3,l1-diketo21 acyloxypregnene (XXII). Hydroxylation at the unsaturation of the lastmentioned compound (XXII) results in the production of 3,11 diketo 17 3),20,21-trihydroxypregnene (XXIII) which is then acylated to form3,11-diketo-l'l ([3) -hydroxy- 2D,21 diacyloxypregnene (XXIV). Whenbrorninated, this compound yields 3,11-diketo-4-bromo-l'l (,6)-hydroxy-20,2ldiacyloxypregnene (XXV).

This compound is then treated with a reagent capable of removing theelements of hydrogen bromide, thereby producing A -3,11-diketo- 17 (p)-hydroxy-20,2l-diacyloxypregnene (XXVI) which on hydrolysis forms A-3,l1-diketo-17- (p),20,21-trihydroxypregnene (XXVII). Partial acylationof this compound (XXVII) gives A 3,11 diketo 1'7 (,8) ,20 dihydroxy 21acyloxypregnene (XXVIII) which, when oxidized, yields a mixture of A-3,l1,20-triketo-17([3) -hydroxy- 21-acyloxypregnene (XXIX) and A-3,11,17- triketo androstene (XXX). Compounds (m) and (XIQC) may beseparated by conventional operations, for example chromatography, andcompounds (XXIX) hydrolyzed to produce the desired adrenal hormone, A-3,11,20-triketo-17- (,8) ,2l-dihydroxypregnene.

This invention is concerned with compounds having basic structuralformulae of the type illustrated by above intermediate 13, together withprocesses of producing same, which intermediate is represented by theformula CH3 CECE in which R is acyl or hydrogen. I

The starting materials employed in the processes according to thisinvention, 3-hydroxy- 11,17-diketoeti0cho1ane or an acyl derivativethereof, may be obtained as described in copending application SerialNo. 649,760, filed February 23, 1946.

In accordance with this invention 3-hydroxy- 11,17-diketoetiocholane oran acyl derivative thereof, is treated with acetylene and an alkalimetal or alkali metal compound capable of replacing one or both of thehydrogen atoms of acetylene with the alkali metal, whereby the 17- 8keto substituent is converted to a substltuent ot the form:

CECE

The reaction preferably is conducted in liquid ammonia or in a tertiaryalcohol. It the 3-.hy-

\ droxy compound is to be converted to the corbe potassium, sodium,lithium, rubidium, cesium;

alkali metal compounds that may be used include alkali metal amides,alkali metal hydrides, alkali metal salts of a tertiary alcohol such asthe tertiary but'yl alcohol or tertiary amyl alcohol, or may be sodiumtriphenyl methyl.

When practicing the process according to this invention, the productobtained is 3,17-dihydroxy- 1l-ketopregnine-20 whether the 3-hydroxy or3- acyloxy compound is treated with acetylene as described. Thestructural formula of this product is as follows:

CHI CECE By esterification of this compound as above mentioned, thecorresponding 3-acyloxy compounds are formed.

The following example, wherein 3(a) -hydroxy- 11,17-diketoetiocholane isconverted to 3(a), 17- (a) -dihydroxy-ll-ketopregnine-20 is oneapplication of the presently inventedprocess to specific reactants, butit will be understood that this example is for purposes of illustrationand that the invention is not limited thereto.

Example To 30-35 cc. of liquid ammonia in a flask, cooled in a dry icebath, is added 1.3 grams of potassium metal. Pure dry acetylene is thenpassed through until the mixture is decolorized. A solution of .5 gramof 3(a) -hydroxy-l1,17-diketoetiocholane in a mixture of 10 cc. ofabsolute dioxane and 10 cc. of absolute ether is their added. Theammonia is permitted to evaporate, 17 cc. of absolute ether added, andthe suspension is closed ofi from the air and left to stand at roomtemperature overnight. The reaction mixture is poured into 3% sulfuricacid, extracted with ether, the ether extract washed with dilutepotassium carbonate and water, the ether removed on the steam bath andthe residue crystallized from ethyl acetate. The pure product, 3(a) ,17-(a)-dihydroxy-11-ketopregnine-20, was obtained in about yield, had amelting point 218.5- 219.0 C. [a] =9.4 (acetone).

8 mg. of pure 3(a),17(a)-dihydroxy-11 ketoanhydride and two drops 01'pyridine at for ten minutes. Water was added; the mixture was extractedfrom ether. The ethereal solution was washed successively with dilutehydrochloric acid, dilute potassium carbonate and with water. Theethereal solution was evaporated to dryness and the residue wascrystallized from ether-petroleum ether. The 3(a) acetoxy 17(oz)hydroxy-llketopregnine was obtained in about 95% yield; it had a meltingpoint of 186-189 C. Other acyl derivatives of the hydroxy compound canbe prepared by substituting other acylating agents for the aceticanhydride above mentioned.

While in the above example the starting material used was a compoundwherein the 3-hydroxy substituent was in the trans form, however acompound having the B-hydroxy substituent in the cis form may be used asthe stearic configuration of the hydroxy group 'is not important.

The temperatures mentioned in the above example are room temperaturesunless otherwise indicated. The temperatures, however, are not criticaland the reactions may be carried out at higher or lower temperatures;but extremely high temperatures should be avoided because of thelikelihood of decomposition of the desired prod ucts which results fromoperation at such temperatures.

Unless otherwise stated, the reagents can be used in differentproportions than are indicated in the above example; the proportionsunless otherwise indicated, are not critical provided enough of thereagents is employed to assure substantially complete reaction toproduce the desired products.

All melting points in this specification are corrected.

Since certain changes in carrying out the above process, and certainmodifications in the inter- OH: CECE O 2. A compound of thecyclopentanoperhydrophenanthrene series having the basic structuralformula:

CH: CECE wherein R is an acetyl group.

3. The process that comprises treating a compound of thecyclopentanoperhydrophenanthrene series having the basic structuralformula:

CH3 0 o OH: I

where in R is of the class consisting of hydrogen and lower aliphaticacyl, with acetylene and a substance of the class consisting of alkalimetals, and obtaining a compound having the basic structural formula:

OH: CECE 4. The process that comprises treating a compound of thecyclopentanoperhydrophenanthrene series having a keto-substituent ineach of the 11 and 17 positions, with acetylene and an alkali metal, andobtaining a corresponding compound of said series having an ll-ketonesubstituent and a 17-position substituent of the form:

CECE

" ammonia 3 hydroxy 11,17 diketoetiocholane with acetylene and potassiumand obtaining 3,17- dihydroxy-11-ketopregnine-20.

8. The process that comprises treating 3(a)-hydroxy-lLl'l-diketoetlocholane with acetylene and potassium in liquidammonia, and obtaining 3(1) .17 (a) -dihydroxy-11-ketopregnine-20.

IEW'ISH-SARETT.

REFERENCES CITED The following references are of record in the me ofthis patent:

UNITED STATES PATENTS Name Date Ruzicka Dec. 23. 1941 Number

